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Principal Investigator: TINEKE CANTAERT
Organization: INSTITUT PASTEUR DU CAMBODGE
Fiscal Year: 2023
Award: $582,693
Funding agency: National Institute of Allergy and Infectious Diseases
We currently have a very limited understanding of the factors, either genetic or immune-related, conferring
protection to clinical Plasmodium vivax (Pv) malaria. Deciphering the mechanisms underlying such protection
would allow the design of tailored intervention strategies for the elimination of Pv. Production of anti-Pv Duffy
Binding Protein (DBP) binding-inhibitory antibodies (BIabs) is associated to functional and protective
immunity against Pv malaria. Only a minority of individuals develops such antibodies and the mechanisms
enabling their production are unknown. Individuals not producing BIabs can still be protected against Pv
clinical malaria indicating that additional immunological and/or genetic factors can confer protection.
Leveraging a longitudinal cohort we have constituted in endemic area of Cambodia, we have identified
individuals displaying remarkable clinical protection against Pv and the overall goal of this proposal aims
at characterizing the factors enabling such protection. The first specific aim (SA1) will be to understand
the factors that drive the production of anti-PvDBP BIabs and therefore further clinical protection against Pv.
By phenotyping and functionally characterizing DBP-specific CD4+ T cells and B cells in naturally infected
participants with characterized amounts of BIabs, we will have a better understanding of the adaptive immune
response of individuals leading to the production of naturally-acquired anti-PvDBP BIabs. On the other hand,
by characterizing the PvDBP allelic polymorphism and isoforms produced by isolates collected from
individuals with various levels of BIabs, we will determine if parasite genetic factors are also contributing to
the acquisition of BIabs. The second and third SA will be to decipher the genetic (SA2) or immune (SA3)
factors leading to protection against Pv malaria for individuals not producing anti-PvDBP BIabs. In SA2, we
will compare the gene expression profiles and genotypes of parasites isolated from chronically-infected
asymptomatic individuals and from symptomatic treatment-seeking patients to identify parasite factors
differentiating these two drastically different clinical outcomes. We will also determine the human erythrocyte
proteins’ polymorphism of individuals displaying contrasted clinical outcome of infection to identify host
genetic factors conferring protection. Any host polymorphism identified will be functionally tested in vitro for
Pv invasion/development alterations. In SA3, we will identify host immune factors associated to protection
from clinical Pv malaria. Using the same patient cohort as SA2, we will study ex vivo and in vitro the immune
responses in Pv-infected patients. Using single cell cultures of antigen-specific B cells, we aim to identify
novel humoral targets on the Pv merozoite or iRBC that could be involved in conferring protection from clinical
Pv malaria trough blockade of invasion or alternative antibody effector functions.
Terms: <Alleles><Allelomorphs><Antibodies><Antigens><Area><Assay><Automobile Driving><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B-cell receptor repertoire sequencing><B-cell receptor sequencing><BCR repertoire sequencing><BCR seq><BCR sequencing><BCRseq><Binding><Binding Proteins><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Sample><Blood erythrocyte><Blood leukocyte><Blood monocyte><Blood reticulocyte><Blood specimen><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cambodia><Cell Body><Cell Culture Techniques><Cells><Characteristics><Chronic><Clinical><Clinical Treatment Moab><Data><Development><Diffusely basophilic erythrocyte><Enabling Factors><Erythrocytes><Erythrocytic><Evidence based intervention><Expression Signature><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Gene Expression><Gene Expression Profile><Genes><Genetic><Genetic Differentiation><Genetic Divergence><Genetic Drift><Genetic Polymorphism><Genome><Genomics><Genotype><Globin><Goals><Human><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Factors><Immunologic Subtyping><Immunological><Immunological Factors><Immunological response><Immunologically><Immunologics><Immunophenotyping><In Vitro><Individual><Infection><Intervention><Intervention Strategies><Invaded><Isoforms><Kampuchea><Khmer Republic><Length><Leukocytes><Leukocytes Reticuloendothelial System><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Long-term cohort><Longitudinal cohort><Longterm cohort><Malaria><Marrow erythrocyte><Marrow leukocyte><Marrow monocyte><Marrow reticulocyte><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Minority><Minority Groups><Minority People><Minority Population><Minority individual><Modern Man><Molecular Interaction><Monoclonal Antibodies><Non-Polyadenylated RNA><Outcome><P vivax><P. vivax><Paludism><Parasites><Participant><Patients><Peptides><Phenotype><Plasmodium Infections><Plasmodium vivax><Plasmodium vivax Malaria><Poly(A)+ mRNA><Polyadenylated mRNA><Polyadenylation Pathway><Polychromatophilic Erythrocyte><Population><Production><Protein Binding><Protein Isoforms><Proteins><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Red Blood Cells><Red Cell><Reticulocytes><Ribonucleic Acid><Sampling><Site><Sorting><Surface><Surface Proteins><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Technology><Testing><Vaccines><Vivax Malaria><White Blood Cells><White Cell><adaptive immune response><blood corpuscles><bound protein><cell culture><cell cultures><cohort><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><differentiation factors><driving><entire genome><flow cytophotometry><full genome><gene expression pattern><gene expression signature><host response><human genome sequencing><immune system response><immunogen><immunologic substance><immunological substance><immunophenotype><immunoresponse><in vitro testing><individual response><individualized response><inhibiting antibody><interventional strategy><mAbs><mRNA><mRNA polyadenylation><monoclonal Abs><monoclonal antibody production><monocyte><morphogenic factors><morphogens><new vaccines><next generation vaccines><novel><novel vaccines><p-Globin><polyadenylated messenger RNA><polymorphism><protection pathway><protective pathway><receptor><resilience><resilient><symptom treatment><symptomatic treatment><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treat symptom><vaccine candidate><vaccine development><white blood cell><white blood corpuscle><whole genome>